Exploring the consequences of the TNFRSF1A susceptibility allele for MS

描述(申请人提供)：我们最近完成了对多发性硬化症(MS)全基因组关联扫描的荟萃分析，并完成了验证几个新的易感基因座的复制工作，包括编码TNF1的两个主要受体之一的TNFRSF1A(rs1800693，P=1.6x10-11)。这一结果很耐人寻味，因为有报道称，多发性硬化症患者在接受抗TNF1单抗治疗后，中枢神经系统炎症加剧。此外，虽然这是第一个确定与炎症性疾病相关的TNFRSF1A的常见变体，但许多不同的罕见变体与被称为TNFRSF1A相关周期综合征(TRAP)的风湿病有关。我们的初步结果表明，rs1800693易感等位基因导致TNFRSF1A外显子6被剪接，产生的跨膜受体缺乏释放可溶性TNFRSF1A所需的切割位点。因此，我们的假设是，rs1800693变异体通过减少产生的可溶性TNFRSF1A的比例增加MS的易感性，从而有效地增加TNF1的活性水平，并可能加剧炎症反应。由于罕见变异在MS中的作用尚不清楚，我们将首先探讨额外的、罕见的TNFRSF1A等位基因是否影响MS的易感性。有了这个全面的遗传评估，我们将探索rs1800693和其他变体对TNFRSF1A剪接和可溶性TNFRSF1A形成的功能后果，以验证我们的假设，即可溶性TNFRSF1A的水平介导了rs1800693对MS易感性的遗传效应。 公共卫生相关性：这项建议的目标是了解TNFRSF1A基因的遗传变异对人类免疫系统功能的影响。该基因的一个变异会增加个人患多发性硬化症的风险。因此，了解它是如何影响人体免疫功能的，将使研究人员能够更好地了解多发性硬化症的发病原因，开发预防多发性硬化症发病的新疗法，并开发可能能够预测谁有患多发性硬化症风险的临床测试。

DESCRIPTION (provided by applicant): We have recently completed both a meta-analysis of genome-wide association scans in multiple sclerosis (MS) and a replication effort that validated several novel susceptibility loci, including TNFRSF1A (rs1800693, P=1.6x10-11) which codes for one of the two principal receptors for TNF1. This result is intriguing in the context of reports of exacerbation of central nervous system inflammation in MS patients following treatment with an anti-TNF1 monoclonal antibody. In addition, while this is the first common variant of TNFRSF1A to be definitively associated with an inflammatory disease, many different rare variants are associated with the rheumatologic disease called TNFRSF1A associated periodic syndrome (TRAPS). Our preliminary results suggest that the rs1800693 susceptibility allele causes TNFRSF1A exon 6 to be spliced, producing a transmembrane receptor that lacks the cleavage site necessary to release the soluble form of TNFRSF1A. Our hypothesis is thus that the rs1800693 variant increases susceptibility to MS by decreasing the proportion of soluble TNFRSF1A that is produced, which effectively increases the level of TNF1 activity and could exacerbate inflammatory responses. Since the role of rare variants is not known in MS, we will first explore whether additional, rare TNFRSF1A alleles influence MS susceptibility. With this comprehensive genetic assessment of the locus in hand, we will then explore the functional consequences of rs1800693 and other variants on TNFRSF1A splicing and the formation of soluble TNFRSF1A to test our hypothesis that the level of soluble TNFRSF1A mediates the genetic effect of rs1800693 on MS susceptibility. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to understand the consequences of genetic variation in the TNFRSF1A gene on the function of the human immune system. A variant in this gene increases an individual's risk for developing multiple sclerosis. Thus, understanding how it affects human immune function will allow investigators to better understand the onset of multiple sclerosis, to develop new treatments to prevent onset of multiple sclerosis, and to develop clinical tests that may be able to predict who is at risk of developing multiple sclerosis.